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Psychopharmacology (Berl). Author manuscript; available in PMC 2012 Dec 1. PMCID: PMC3308357
Published in final edited form as: NIHMSID: NIHMS347884
Psychopharmacology (Berl). 2011 Dec; 218(4): 649–665. PMID: 21674151
Published online 2011 Jun 15. doi: 10.1007/s00213-011-2358-5

Psilocybin occasioned mystical-type experiences: Immediate and persisting dose-related effects

R. R. Griffiths, M.W. Johnson, W. A. Richards, B.D. Richards, U. McCann, and R. Jesse

Abstract

Rationale

This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting posi‐
tive effects on attitudes, mood, and behavior.

Objectives

This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions.
Methods

Participants were 18 adults (17 hallucinogen-naïve). Five 8-hour sessions were conducted individually for each participant at 1-month inter‐
vals. Participants were randomized to receive the four active doses in either ascending or descending order (9 participants each). Placebo was
scheduled quasi-randomly. During sessions volunteers used eyeshades and were instructed to direct their attention inward. Volunteers com‐
pleted questionnaires assessing effects immediately after and 1 month after each session, and at 14 months follow-up.

Results

Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers)
and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin expe‐
rience as having substantial personal and spiritual significance, and attributed to the experience sustained positive changes in attitudes, mood,
and behavior, with the ascending dose sequence showing greater positive effects. At 14 months, ratings were undiminished and were consis‐
tent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing
function of dose, with the lowest dose showing significant effects.

Conclusions

Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting positive effects on atti‐
tudes, mood and behavior. Implications for therapeutic trials are discussed.

Keywords: psilocybin, dose-effects, hallucinogen, entheogen, psychedelic, mystical experience, fear, spiritual, religion, positive psychology,
humans

Introduction

Psilocybin, which is the principal psychoactive component of Psilocybe and other genera of mushrooms, has likely been used for millennia
within some cultures in structured manners for divinatory or religious purposes (Wasson, 1980; Stamets 1996; Metzner 2004; Guzmá n 2008).
Like other classic hallucinogens (d-lysergic acid diethylamide [LSD], mescaline, N,N-dimethyltryptamine [DMT]), the effects of psilocybin are
primarily mediated at 5-HT2A receptor sites (Glennon et al. 1984; Nichols 2004), and the acute subjective effects include robust changes in per‐
ception, cognition, affect, volition, and somesthesia (Isbell 1959; Wolbach et al. 1962; Rosenberg et al. 1964). In early clinical research with
psilocybin, the affective character of subjective experiences often varied from positive to negative, and highly valued personal or mystical-type
experiences were rare (e.g., Isbell 1959; Malitz et al. 1960; Rinkel et al. 1960; Hollister 1961). Subsequent research that generally used higher
psilocybin doses and provided more preparation and interpersonal support reported a higher rate of affectively positive experiences, some‐
times of a mystical nature, that were rated as being of personal significance (Leary et al. 1963; Metzner et al. 1965; Pahnke 1969).

Recently, we used rigorous double-blind methods to evaluate the acute (7 hour) and longer-term (2 months and 14 months) psychological ef‐
fects of a high dose of psilocybin (30 mg/70 kg) relative to an active comparison compound (40 mg/70 kg methylphenidate) in 36 hallucino‐
gen-naïve volunteers (Griffiths et al. 2006, 2008). The study was designed to optimize the potential for positively-valued experiences by pro‐
viding eight hours of preparation, administering psilocybin in a pleasant, supportive setting, and instructing volunteers to focus explicitly on
their subjective or inner experience rather than, for example, perform tasks. The results showed that psilocybin occasioned mystical-type ex‐
periences and, sometimes, significant fear. The mystical-type experiences were rated as having substantial and persisting personal meaning
and spiritual significance to which volunteers attributed sustained positive changes in attitudes, moods and behavior. The present study was
undertaken using similar procedures to characterize the acute and persisting effects of a range of lower doses of psilocybin (0, 5, 10, 20, 30
mg/70 kg). The study was also designed to compare the ascending and descending sequences of drug dose exposure.

Materials and methods

Participants

Participants were recruited from the local community through flyers announcing a study of states of consciousness brought about by psilocy‐
bin, a naturally occurring psychoactive substance used sacramentally in some cultures. Two hundred seventy-nine individuals were screened
over the telephone and 31 were further screened in person. The 18 study participants (8 males) were medically healthy (as determined by
medical history, physical examination, an electrocardiogram, routine medical blood laboratory tests, and urine testing for common drugs of
abuse), psychiatrically healthy, and without family histories of psychotic disorders or bipolar I or II disorder (as determined by structured clin‐
ical interviews). Individuals with current alcohol or drug dependence (including nicotine) were excluded, as were individuals with a past his‐
tory within the past 20 years of alcohol or drug dependence (excluding nicotine). Participants were hallucinogen naïve, except for one who re‐
ported using psilocybin mushrooms on two occasions more than 20 years previously. Participants had an average age of 46 years (range 29 to
62) and were well-educated; all had at least some college, 94% were college graduates, and 56% had post-graduate degrees. Fifty-six percent
were employed full-time, 33% part-time, and 11% were retired. Fifty percent indicated affiliation with a religious or spiritual community, such
as a church, synagogue, or meditation group. While not an inclusion criterion, all 18 volunteers indicated at least intermittent participation in
religious or spiritual activities such as religious services, prayer, or meditation, with 39% reporting daily activities and an additional 39% re‐
porting at least weekly activities. Volunteers did not receive monetary compensation for participation. Based on interviews, their motivation
for participation was curiosity about the effects of psilocybin and the opportunity for extensive self-reflection in the context of the day-long
drug sessions and the meetings with the monitors that occurred before and after sessions. The Institutional Review Board of the Johns
Hopkins University School of Medicine approved the study, and all volunteers gave their informed consent before participation.

Study design and overview

The study procedures followed recommendations provided for safe conduct of research administering high doses of a classic hallucinogen
(Johnson et al. 2008). The study examined psilocybin (0, 5, 10, 20, and 30 mg/70 kg) using a double-blind, between-group, crossover design
that involved five 8-hour drug sessions conducted at approximately 1-month intervals, and a 14-month follow-up. Eighteen volunteers were
randomly assigned to receive the active psilocybin doses in either an ascending dose sequence or a descending sequence. Although each vol‐
unteer received the 0 mg/70 kg condition once, across the 9 volunteers in each of the ascending and descending sequences, the 0 mg/70kg
condition occurred twice on sessions 1, 2, 4, and 5, and once on session 3. The purpose of this quasi-random scheduling of placebo was to ob‐
scure the dose sequence to the participants and monitors (see Instructions section below). Outcome measures obtained throughout the drug
sessions included blood pressure and monitor ratings of participant mood and behavior. At about 7 hours after drug ingestion (when the pri‐
mary drug effects had subsided), participants completed several questionnaires designed to assess various aspects of hallucinogen experience
(described below). Various longitudinal and persisting effects measures were assessed at screening, 1 month after each drug session, and at
14 months after the last session.

Instructions to participants and monitors

Participants and monitors were informed that participants would receive placebo and four different doses (ranging from low to high) of psilo‐
cybin in mixed order across sessions. Neither participants nor monitors were informed that the active psilocybin doses would be tested in an
ascending or descending sequence. The only exception to this was that two of the seven assistant monitors were not blind to the
ascending/descending nature of the experimental design, however they were blind to the outcome of randomization.

Drug conditions

Psilocybin doses and placebo (0 mg/70 kg) were prepared in identically-appearing opaque, size 0 gelatin capsules, with lactose as the inactive
capsule filler. On each session, a single capsule was administered with 180 ml water.

Meetings with monitor before and after sessions

The primary monitor (usually along with the assistant monitor) met with each participant on four occasions before his or her first session (for
8 hours total), once for about an hour on the day following each of the five sessions, and one more time about 3 weeks after each session. The
purpose and content of these meetings are described elsewhere (Griffiths et al. 2006; Johnson et al. 2008). Monitors and assistant monitors
were trained by personnel with extensive prior experience monitoring hallucinogen sessions.

Drug Sessions

As described in more detail previously (Griffiths et al. 2006), drug sessions were conducted in an aesthetic living-room-like environment with
two monitors present. Participants were instructed to consume a low-fat breakfast before coming to the research unit. A urine sample was
taken to verify abstinence from common drugs of abuse (cocaine, benzodiazepines, and opioids including methadone). Although the presence
of THC was not tested, none of the volunteers reported recent use of cannabis. For most of the time during the session, participants were en‐
couraged to lie down on the couch, use an eye mask to block external visual distraction, and use headphones through which a music program
was played. The same music program was played for all participants in all sessions. Participants were encouraged to focus their attention on
their inner experiences throughout the session.

Measures assessed throughout the session

Ten minutes before and 30, 60, 90, 120, 180, 240, 300, and 360 minutes after capsule administration, blood pressure, heart rate, and monitor
ratings were obtained.

Blood pressure and heart rate Blood pressure (systolic and diastolic pressure using oscillometric method with the blood-pressure cuff placed
on the arm) and heart rate were monitored using a Non-Invasive Patient Monitor Model 507E (Criticare Systems, Inc., Waukesha, WI).

Monitor Rating Questionnaire At the same time-points at which the physiological measures were taken, the two session monitors completed
the Monitor Rating Questionnaire, which involved rating or scoring several dimensions of the participant’s behavior or mood (Table 1). The di‐
mensions that are expressed as peak scores in Table 1 were rated on a 5-point scale from 0 to 4. Dimensions expressed as total duration in
Table 1 were rated as the estimated number of minutes since the last rating. Data were the mean of the two monitor ratings at each time-point.

Measures assessed 7 hours after drug administration

At about 7 hours after capsule administration when the major drug effects had subsided, the participant completed three questionnaires de‐
veloped for assessing the subjective effects of hallucinogen drugs and two questionnaires developed for assessing mystical experience.
Participants typically completed these questionnaires in about 40 minutes.

Hallucinogen Rating Scale This 99 item questionnaire, which was designed to show sensitivity to the hallucinogen N,N-dimethyltryptamine
(DMT) (Strassman et al. 1994), consists of six subscales assessing various aspects of hallucinogen effects (Intensity, Somaesthesia, Affect,
Perception, Cognition, and Volition).

APZ The APZ is a 72 item yes/no questionnaire designed to assess altered states of consciousness, including those produced by hallucinogens
(Dittrich 1998). The three major scales on the APZ are the OSE (oceanic boundlessness; a state common to classic mystical experiences includ‐
ing feelings of unity and transcendence of time and space), the AIA (dread of ego dissolution; dysphoric feelings), and the VUS (visionary re‐
structuralization; includes items on visual pseudo-hallucinations, illusions, and synesthesias). Data on each scale were expressed as a propor‐
tion of the maximum possible score.

Addiction Research Center Inventory (ARCI) The ARCI was developed to differentiate subjective effects among several classes of psychoactive
drugs including the hallucinogens (Haertzen 1966). The short form of the ARCI consists of 49 true/false questions and contains five major
scales: lysergic acid diethylamide (LSD), a hallucinogen-sensitive scale that is often interpreted as providing a measure of dysphoric changes;
pentobarbital, chlorpromazine, alcohol group (PCAG), a sedative sensitive scale; benzedrine group (BG) and amphetamine (A) scales, ampheta‐
mine-sensitive scales; and morphine-benzedrine group (MBG), often interpreted as a measure of euphoria (Martin et al. 1971; Jasinski 1977).
Participants were instructed to answer the questions on the ARCI with reference to the effects they experienced since they received the cap‐
sule that morning.

States of Consciousness Questionnaire This 100 item questionnaire is rated on a 6-point scale [0=none; not at all; 1=so slight cannot decide;
2=slight; 3=moderate; 4=strong (equivalent in degree to any previous strong experience or expectation of this description); 5=extreme (more
than ever before in my life and stronger than 4)]. Forty-three items on this questionnaire comprised the current version of the Pahnke-
Richards mystical experience items, which was shown sensitive to psilocybin (Electronic Supplementary Table 1 in Griffiths et al. 2006). An ear‐
lier version of this scale was also previously shown sensitive to psilocybin and other hallucinogens (Pahnke 1963; Turek et al. 1974; Richards
et al. 1977). The 43 items provide scale scores for each of seven domains of mystical experiences: internal unity (pure awareness; a merging
with ultimate reality); external unity (unity of all things; all things are alive; all is one); sense of sacredness (reverence; sacred); noetic quality
(claim of an encounter with ultimate reality; more real than everyday reality); transcendence of time and space, deeply-felt positive mood (joy,
peace, love); paradoxicality and ineffability (claim of difficulty in describing the experience in words). Data on each domain scale were ex‐
pressed as a percentage of the maximum possible score. As in previous studies (Pahnke 1969; Griffiths et al. 2006), criteria for designating a
volunteer as having had a “complete” mystical experience were that scores on each of the following six scales had to be at least 60%: unity (ei‐
ther internal or external, whichever was greater), sense of sacredness, noetic quality, transcendence of time and space; positive mood; and in‐
effability. A mean total score was calculated as a mean of all items from the preceding six scales. The remaining 57 items in the States of
Consciousness Questionnaire served as distracter items.

Mysticism Scale (Experience-specific) This 32-item questionnaire, which assesses primary mystical experiences, has been extensively studied
and shows cross-cultural reliability (Hood et al. 2001, 2009) and has previously been shown sensitive to psilocybin (Griffiths et al. 2006). A to‐
tal score and three empirically-derived factors are measured: Interpretation (corresponding to three mystical dimensions: noetic quality, sa‐
credness, and deeply felt positive mood); Introvertive Mysticism (corresponding to the mystical dimensions of internal unity, transcendence of
time and space, and ineffability); Extrovertive Mysticism (corresponding to the dimension of the unity of all things/all things are alive). Items
were rated on a 9-point scale (Griffiths et al. 2006). For this experience-specific version of the questionnaire used 7 hours after drug adminis‐
tration, participants were instructed to complete the questionnaire with reference to their experiences since they received the capsule that
morning.

Persisting effects assessed one month after sessions

At 3 to 4 weeks after each session, and before any additional session, participants returned to the research facility and completed a series of
questionnaires to assess possible changes in various standardized measures of personality, mood, and spirituality (not included in this report)
as well as possible persisting changes in attitudes, mood, behavior, and spirituality. Participants typically completed these questionnaires in
about 75 minutes.

Persisting Effects Questionnaire This 143-item questionnaire sought information about changes in attitudes, moods, behavior, and spiritual ex‐
perience that, on the basis of prior research (Pahnke 1969; Doblin 1991, Griffiths et al. 2006), would be sensitive to the effects of psilocybin a
month after the session. One hundred forty of the items were rated on a 6-point scale (0=none, not at all; 1=so slight cannot decide; 2=slight;
3=moderate; 4=strong; 5=extreme, more than ever before in your life and stronger than 4). Within the questionnaire, the items were labeled
in six categories: Attitudes about life (13 positive and 13 negative items); Attitudes about self (11 positive and 11 negative items); Mood
Changes (9 positive and 9 negative items); Relationships (9 positive and 9 negative items); Behavioral changes (1 positive and 1 negative item);
Spirituality (22 positive and 21 negative items). The positive and negative items were intermixed within each category. For purposes of scoring
the resulting 12 scales (positive and negative scales for each of 6 categories) scores were expressed as the percentage of the maximum possi‐
ble score. The version of the questionnaire used (available from the authors upon request) was an expanded version of that described by
Griffiths et al. 2006. Scale scores on the original and the expanded version were highly correlated (.958-.997) on scales showing reasonable
variability. Scales measuring negative effects did not have enough responses and therefore did not have enough variability for these calcula‐
tions to be meaningful.
The questionnaire included three additional questions (see Griffiths et al. 2006 for more specific wording): 1). How personally meaningful was
the experience? (rated from 1-8, with 1=no more than routine, everyday experiences; 7=among the 5 most meaningful experiences of my life;
and 8=the single most meaningful experience of my life). 2). Indicate the degree to which the experience was spiritually significant to you?
(rated from 1 to 6, with 1=not at all; 5=among the 5 most spiritually significant experiences of my life; 6=the single most spiritually significant
experience of my life). 3). Do you believe that the experience and your contemplation of that experience have led to change in your current
sense of personal well-being or life satisfaction? (rated from +3=Increased very much; 0=No change; −3=Decreased very much).

Retrospective persisting effects assessed at 14-month follow-up

At 14 months after the last session, participants completed a Retrospective Questionnaire and an open-ended clinical interview reflecting on
study experiences and current life situation. For purposes of completing the Retrospective Questionnaire, volunteers were reminded that over
the 5 sessions they had received 4 different doses of psilocybin. They were then informed on which two sessions they had received the two
highest doses of psilocybin, although they were not informed which of the two was the highest dose. One hundred forty-three items comprised
the previously described Persisting Effects Questionnaire. For these items, volunteers were asked to rate any current persisting effects that
they attribute to the experiences during either or both the two highest dose sessions. Volunteers were also asked to provide written descrip‐
tions about the session experiences, including how their behavior changed in response to the experiences. Forty-three items on this question‐
naire were the previously described mystical experience items from the States of Consciousness Questionnaire, which were completed twice --
looking back separately on each of the two sessions associated with the two highest doses. In four final questions, participants were asked, of
all five sessions, which session was associated with the strongest effect, which was most personally meaningful, which was most spiritually sig‐
nificant, and which would they chose to repeat if they had the opportunity to do so.

Longitudinal measures assessed at baseline, after session 5, and at 14-month follow-up

More than a dozen longitudinal measures were assessed at screening or shortly after enrollment, after sessions, and at the 14-month follow-
up. The results from most of these measures will be combined with results from a previous study (Griffiths et al. 2006) and reported sepa‐
rately. Three measures are reported here.

Mysticism Scale (Lifetime) Participants were instructed to complete this previously described questionnaire with reference to their lifetime
experience.
Death Transcendence Scale The 26-item Death Transcendence Scale (Hood and Morris, 1983; VandeCreek, 1999) was administered because a
potentially important clinical application of psilocybin is in treatment of individuals who are anxious or depressed in response to terminal ill‐
ness (Grob et al. 2011). Items were rated on a 9-point scale and five subscales were scored: Mysticism, Religious, Nature, Creative, and
Biosocial.

Community Observer Ratings of Changes in Participants’ Behavior and Attitudes This previously described measure was shown sensitive to
psilocybin 2 months after a high dose session (Griffiths et. al., 2006). After acceptance into the study, each participant designated as raters
three adults who were expected to have continuing contact with the participant (e.g. family members, friends, or colleagues at work). Ratings
were conducted via a structured telephone interview approximately 1 week after the participant had been accepted into the study, 3 to 4
weeks after the last session, and as part of the 14-month follow-up. The interviewer provided no information to the rater about the partici‐
pant. The structured interview consisted of asking the rater to rate the volunteer’s behavior and attitudes using a 10 point scale (from 1=not
at all, to 10=extremely) on eleven items: inner peace; patience; good-natured humor/playfulness; mental flexibility; optimism; anxiety; inter‐
personal perceptiveness and caring; negative expression of anger; compassion/social concern; expression of positive emotions (e.g. joy, love,
appreciation); and self-confidence. On the first rating occasion, which occurred soon after acceptance into the study, raters were instructed to
base their ratings on observations of and conversations with the participant over the past 3 months. On subsequent assessments, raters were
told their previous ratings and were instructed to rate the participant based on interactions over the last several weeks. Data from each inter‐
view with each rater were calculated as a total score, with anxiety and anger scored negatively. Changes in each participant’s behavior and atti‐
tudes after drug sessions were expressed as a mean change score (i.e. difference score) from the baseline rating across the raters. Rating com‐
pletion rate was 96%; seven ratings were missed due to a failure to return calls or to the rater not having contact with the volunteer over the
rating period.

Post-study monitor ratings of enduring effects in participants

At the conclusion of the study, the primary and assistant monitor for each volunteer were asked to assess any enduring changes in the
volunteer’s attitudes and behaviors that the monitor believed resulted directly or indirectly from the psilocybin session experiences in the
study. Three ratings were done on a 7-point scale (−3=decreased very much; 0=No change; +3=increased very much): 1. Change in volunteer’s
sense of personal well-being or life satisfaction; 2. Change in quality of volunteer’s social relationships (e.g. spouse, family, friends and acquain‐
tances); and 3. Change in the volunteer’s sense of spirituality, broadly construed. Score for each volunteer was the mean of the primary and
assistant guide ratings for each question.

Data Analyses
Cardiovascular and Monitor Ratings assessed throughout the session Two sets of analyses were conducted. For the time-course data, Planned
Comparisons were conducted comparing the effect of each of the active psilocybin doses with 0 mg/70 kg at each time-point. For the second
set of analyses, for each participant, peak scores during the time-course were defined as the maximum value from pre-capsule to 6 hr post-
capsule, and temporal measures (e.g. minutes talking or sleeping) were summed across the 8 post-capsule time-points. A repeated measures
regression model with AR(1) covariance structure was used with Dose (0, 5, 10, 20, 30 mg/70 kg), Time (10 min before and 0.5, 1, 1.5, 2, 3, 4,
5, and 6 hr after capsule administration), Dose Sequence (ascending vs. descending), and interactions among these as the effects in the model.
Fisher’s LSD post-hoc tests were used to compare the drug conditions. Two of the seven assistant guides were not blind to the
ascending/descending nature of the experimental design, so the analysis described above was repeated excluding ratings from these two mon‐
itors. Because there were no differences in the statistical significance of Sequence or Sequence interactions and only minor other differences
occurred, the data presented are from all monitor ratings.

Measures assessed 7 hours after drug administration and measures assessed one month after sessions For the hallucinogen-sensitive question‐
naires and the mystical experience questionnaires assessed 7 hours after sessions and for the Persisting Effects Questionnaire assessed one
month after sessions, a repeated measures regression was used with Dose (0, 5, 10, 20, 30 mg/70 kg) and Dose Sequence (ascending vs. de‐
scending) and their interaction as effects in the model. Fisher’s LSD post-hoc tests were used to compare the drug conditions. For analysis of
dichotomous responses across the five drug conditions for measures shown in Table 5 (Persisting Effects Questionnaire), Cochran’s Q, a non-
parametric, binary repeated measures test, was conducted with a factor of Dose (0, 5, 10, 20, 30 mg/70 kg). Planned comparisons for these
data were conducted using Wald chi square tests to compare active doses to 0 mg/70 kg.

Retrospective persisting effects assessed at 14 month follow-up For analysis of the eight scales from the mystical experience items of the States
of Consciousness Questionnaire, a repeated measures regression was used with Condition (7 hours after 0 mg/70 kg; 7 hours after 30 mg/70
kg; and 14 month retrospective for 30 mg/70 kg), Dose Sequence, and their interaction as effects in the model. Fisher’s LSD post-hoc tests
were used to compare the conditions. For analysis of dichotomous responses across three sets of conditions (1 month after 0 mg/70 kg; com‐
bined data for 1 month follow-ups after both the 20 and 30 mg/70 kg dose sessions; 14 month follow-up data for retrospective rating for ei‐
ther or both the 20 and/or 30 mg/70 kg dose sessions), Cochran’s Q was conducted with a factor of Condition (the three conditions described
above). Planned comparisons were conducted using Wald chi square tests to compare the three conditions.

Longitudinal measures assessed at screening, after session 5, and at 14-month follow-up For analysis of the measures of mystical experience, of
death transcendence, and of community observer ratings of changes in participants’ behavior and attitudes assessed at screening, 1 month af‐
ter session 5, and at 14-month follow-up, a repeated measures regression was used with Time (screening, after session 5, and 14-month fol‐
low-up) and Dose Sequence and their interaction as effects in the model. Planned comparisons were used to compare screening values with
the two post-drug time points.
For all statistical analysis, results were considered significant at p <.05.

Results

Integrity of blinding procedures

At the conclusion of the study, the primary and assistant guides completed a questionnaire that asked about their understanding of the experi‐
mental design. None of the three primary guides or the five assistant guides who were blind the ascending or descending nature of the doses
sequences guessed or reported awareness of this aspect of the study procedures.

Cardiovascular measures and monitor ratings assessed throughout the session

Psilocybin produced significant and orderly dose- and time-related effects on cardiovascular measures and monitor ratings assessed through‐
out the session. At the two highest doses (20 and 30 mg/70kg), onset of significant effects generally occurred at the 30- or 60-minute assess‐
ment, with effects usually peaking from 90 to 180 minutes and decreasing toward pre-drug levels over the remainder of the session (see
Figure 1 for illustrative measures). Table 1 shows the mean effects at each dose for these measures. For measures sensitive to psilocybin, ef‐
fects were generally a monotonically increasing function of dose. For most measures, the 5 mg/70 kg dose was significantly greater than
placebo and the 20 and/or 30 mg/70 kg dose(s) were significantly greater than the lower active doses. There were no significant Sequence or
Dose x Sequence interactions. The blood pressures of the four volunteers who had the highest pressures 60 minutes or longer after the 30
mg/70 kg psilocybin were: 187/84, 166/64, 182/88, and178/95 mmHg. These pressures were considered high enough to warrant further re‐
peated blood pressure assessment, however they were not judged to be of sufficient magnitude to necessitate pharmacological treatment.

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Fig. 1

Within session time-course of psilocybin. Systolic and diastolic blood pressure and monitor ratings of overall drug effect, and joy/intense happiness as a function of time
since capsule ingestion (time 0 = before drug administration). Data points are means; filled data points indicate a significant difference from 0 mg/70 kg at the indicated
time point (Planned Comparisons).
Table 1

Cardiovascular measures and monitor ratings of volunteer behavior and mood assessed throughout the session*

Psilocybin Dose (mg/70 kg)

Measure
0 5 10 20 30

Cardiovascular Measures (peak effects)

Systolic blood pressure (mm Hg) 132.6 (3.6) 143.3 (4.3)a 145.7 (4.6)a 145.7 (4.2)a 153.1 (4.2)b

Diastolic blood pressure (mm Hg) 77.5 (1.9) 83.4 (2.1)a 83.9 (2.0)a 84.3 (2.5)a 88.8 (2.4)b

Heart rate (beats per minute) 74.8 (2.5) 78.7 (2.7)a 77.9 (2.0)a 81.2 (3.0)a,b 83.0 (2.4)b

Monitor Ratings (peak effects, max score=4)

Overall drug effect 0.69 (0.15) 2.03 (0.13)a 2.44 (0.19)b 3.06 (0.15)c 3.42 (0.15)c

Sleepiness/sedation 1.11 (0.22) 0.69 (0.18) 0.78 (0.20) 0.58 (0.16) 0.58 (0.14)

Unresponsive to questions 0.17 (0.09) 0.19 (0.12)a 0.44 (0.14)b 0.97 (0.30)c 1.14 (0.24)d

Anxiety or Fearfulness 0.28 (0.10) 0.61 (0.19)a 0.75 (0.15)b 1.06 (0.22)c 1.19 (0.22)d

Stimulation/arousal 0.53 (0.19) 1.19 (0.13)a 1.64 (0.19)b 1.97 (0.20)b,d 2.17 (0.22)c,d

Distance from ordinary reality 0.75 (0.17) 1.92 (0.19)a 2.36 (0.21)b 2.97 (0.17)c 3.22 (0.15)c

Ideas of reference/paranoid thinking 0.03 (0.03) 0.00 (0.00)a 0.08 (0.05)a 0.14 (0.06)a 0.44 (0.14)b

Yawning 0.22 (0.10) 0.53 (0.15)a 0.97 (0.27)a,b 1.36 (0.37)b,c 1.81 (0.39)c

Tearing/crying 0.61 (0.24) 1.00 (0.29)a 1.25 (0.26)b 1.50 (0.33)c 1.81 (0.24)d

Nausea 0.00 (0.00) 0.33 (0.10)a 0.42 (0.15)b 0.31 (0.13)c 0.47 (0.13)d

Spontaneous motor activity 0.22 (0.09) 0.64 (0.15)a 0.78 (0.20)a 1.14 (0.32)a,c 1.47 (0.35)b,c

Restless/fidgety 0.17 (0.07) 0.44 (0.18)a 0.58 (0.12)b 0.89 (0.19)c 0.81 (0.17)d

Joy/Intense happiness 0.64 (0.19) 1.19 (0.22)a 1.42 (0.27)a,b 1.81 (0.33)b,c 2.14 (0.31)c

Peace/harmony 0.78 (0.19) 1.39 (0.22)a 1.64 (0.22)a,b 2.11 (0.30)b 2.03 (0.27)b

Monitor Ratings (total duration in minutes max score=360)

 *
Data are means with 1 SEM shown in parentheses (N=18); within a row, bold font indicates significant difference from 0 mg/70 kg; for active doses, values not sharing a
common letter are significantly different (Fisher’s LSD p<0.05)
†
e.g., reassuring touch

Drug effect and mysticism measures assessed 7 hours after drug administration

Subjective effects questionnaires The three questionnaires developed for sensitivity to the subjective effects of hallucinogens showed orderly
dose-related increases (Table 2). All six scales of the Hallucinogen Rating Scale, all three scales on the APZ Questionnaire, and the A and LSD
scales of the ARCI showed significant and monotonically increasing effects as a function of dose, with significant effects on most measures at
even the lowest dose of 5 mg/70 kg. These effects, which are typical of hallucinogens, include perceptual changes (e.g. visual pseudo-hallucina‐
tions, illusions, and/or synesthesias), labile moods (e.g. feelings of transcendence, grief, joy, and/or anxiety), and cognitive changes (e.g. sense
of meaning, insight, and/or ideas of reference). There were no significant Sequence or Sequence x Dose interactions.
Table 2

Volunteer ratings on three subjective effects questionnaires completed 7 hours after drug administration*

Questionnaire and Subscale Psilocybin Dose (mg/70 kg)

Description 0 5 10 20 30

Hallucinogen Rating Scale

Intensity 0.94 (0.17) 1.85 (0.15)a 2.50 (0.14)b 2.64 (0.15)b 2.69 (0.13)b

Somaesthesia 0.35 (0.07) 1.32 (0.14)a 1.56 (0.16)a 1.91 (0.17)b 2.12 (0.15)b

Affect 0.93 (0.11) 1.48 (0.16)a 1.76 (0.16)a,b 1.95 (0.14)b,c 2.16 (0.16)c

Perception 0.23 (0.07) 1.14 (0.16)a 1.38 (0.18)a 1.72 (0.17)b 2.09 (0.20)c

Cognition 0.70 (0.14) 1.33 (0.20)a 1.63 (0.18)a 2.08 (0.19)b 2.26 (0.22)b

Volition 1.04 (0.08) 1.52 (0.12)a 1.69 (0.11)a,b 1.79 (0.12)b 1.81 (0.16)b

APZ Questionnaire

OSE (oceanic boundlessness) 2.67 (0.56) 5.72 (0.76)a 5.89 (0.76)a,c 7.22 (0.70)b,c 8.33 (0.73)b

AIA (dread of ego dissolution) 0.50 (0.24) 2.50 (0.79)a 3.11 (0.65)a,c 4.17 (0.61)b,c 4.89 (0.84)b

VUS (visionary restructuralization) 1.78 (0.48) 6.06 (0.82)a 7.28 (0.64)a,b 7.67 (0.68)b 8.44 (0.82)b

Addiction Research Center Inventory (ARCI)

PCAG (sedative) 5.28 (0.50) 6.28 (0.87) 7.22 (0.81) 6.78 (0.80) 7.22 (0.96)

BG (amphetamine/self-control) 4.94 (0.36) 4.83 (0.38) 5.56 (0.60) 5.06 (0.55) 4.72 (0.53)

A (amphetamine) 2.78 (0.35) 4.94 (0.39) 5.17 (0.52) 4.83 (0.48) 5.06 (0.62)

MBG (euphoria) 5.61 (0.86) 8.11 (1.05) 8.06 (0.84) 7.89 (0.90) 8.28 (1.13)

LSD (hallucinogen/dysphoria) 2.56 (0.29) 6.06 (0.64)a 6.39 (0.64)a,c 7.39 (0.65)b,c 7.83 (0.57)b

*
Data are mean scores with 1 SEM shown in parentheses (N=18); within a row, bold font indicates significant difference from 0 mg/70 kg; for active doses, values not
sharing a common letter are significantly different (Fisher’s LSD p<0.05)
Measures of mystical experience Also at 7 hours after capsule administration, volunteers completed two questionnaires designed to assess
mystical experience (Table 3). The total score and all three empirically-derived factors of the Mysticism Scale and all seven scales on States of
Consciousness Questionnaire showed significant and monotonically increasing effects as a function of dose, with significant effects at the 5
mg/70 kg dose. The proportion of volunteers who met a priori criteria for having had a “complete” mystical-type experience on the States of
Consciousness Questionnaire was also an increasing function of dose: 0, 5.6, 11.1, 44.4, and 55.6% at 0, 5, 10, 20, and 30 mg/70kg, respec‐
tively. Overall, 72.2% of volunteers had “complete” mystical experiences at either or both the 20 and 30 mg/70 kg session. Only the Mysticism
Scale showed an effect of Sequence or a Dose x Sequence interaction. This effect was largely due to differences in response to placebo.
Examination of the position of the placebo condition within the sequence suggested this result was spurious.
Table 3

Volunteer ratings on two mystical experience questionnaires completed 7 hours after drug administration and at 14 month follow-up*

7 Hours after Drug Administration 14 Month

Questionnaire and Subscale
Psilocybin Dose (mg/70 kg) Follow-up
Description
0† 5† 10 † 20 † 30 † (30 mg/70 kg) ‡

States of Consciousness Questionnaire

Internal unity 15.2 (4.6) 38.0 (6.7)a 44.6 (5.07)a 64.4 (6.0)b 70.2 (6.2)b 76.5 (6.4)

External unity 12.4 (3.7) 32.6 (6.0)a 35.0 (6.0)a 53.3 (5.6)b 60.7 (6.7)b 63.5 (7.4)

Sacredness 23.7 (5.5) 48.7 (6.9)a 54.0 (6.4)a 71.1 (5.8)b 77.1 (6.4)b 83.3 (4.7)

Noetic Quality 19.4 (5.3) 47.5 (6.7)a 54.4 (5.8)a,b 65.3 (6.0)b,c 70.6 (6.5)c 76.9 (6.4)

Transcendence of time and space 18.3 (4.8) 40.4 (6.8)a 44.4 (5.6)a 65.4 (6.2)b 78.2 (5.2)c 82.6 (5.2)

Deeply felt positive mood 26.8 (4.7) 47.6 (5.4)a 57.5 (6.3)a,b 68.3 (5.5)b,c 73.2 (6.5)c 77.3 (5.7)

Ineffability 19.3 (6.0) 48.4 (6.3)a 59.1 (5.8)a 73.1 (6.6)b 81.3 (6.0)b 81.1 (4.6)

Total 21.0 (4.7) 45.1 (5.9)a 52.0 (5.2)a 68.3 (5.0)b 75.6 (5.4)b 80.1 (4.9)

Mysticism Scale

Interpretation 57.1 (6.5) 83.5 (5.3)a 84.1 (5.2)a 95.7 (3.7)b 99.1 (2.6)b N/A

Introvertive 54.4 (7.1) 77.6 (6.2)a 79.7 (5.1)a 93.0 (3.7)b 97.4 (3.4)b N/A

Extrovertive 30.7 (4.7) 48.2 (4.7)a 49.4 (5.0)a 57.1 (3.9)b 61.3 (3.8)b N/A

Total (max score=288) 142.2 (17.7) 209.2 (15.4)a 213.2 (14.4)a 245.8 (9.0)b 257.9 (8.9)b N/A

*
Data are mean scores with 1 SEM shown in parentheses (N=18); data for the States of Consciousness Questionnaire are expressed as a percentage of the maximum
possible score
†
Data in these columns show rating data 7 hours after the indicated dose of psilocybin; within the same row for these columns, bold font indicates significant difference
from 0 mg/70 kg; for active doses, values not sharing a common letter are significantly different (Fisher’s LSD p<0.05)
 ‡
For the States of Consciousness Questionnaire, data in this column show ratings of the 30 mg/70 kg session experience at the 14 month follow-up; each value in this
column was significantly greater than the value at 0 mg/70 kg after 7 hours (as indicated by bold font) but was not different from the value at 30 mg/kg 1 month (Fisher’s
LSD p<0.05); 14 month follow-up data were not obtained for the experience-specific version of the Mysticism Scale (indicated by N/A), although data were obtained for
the Lifetime version (see text)

Psilocybin-Induced Fear/Anxiety or Delusions

Although volunteers were carefully screened and psychologically prepared, and close interpersonal support was provided during sessions, on
questionnaires completed at the end of the session, 39% of participants (7 of 18) had extreme ratings of fear, fear of insanity or feeling
trapped at some time during the session. Such episodes occurred in 6 of 7 of these participants after the 30 mg/70 kg dose and in 1 of 7 after
the 20 mg/70 kg dose. Monitor ratings of peak anxiety/fear during the session showed dose-rated increases, with each dose producing a sig‐
nificantly higher rating than the lower doses (Table 1). After 30 mg/70 kg, monitor ratings of anxiety/fear across the session showed varying
time-courses of onset and duration, with peak effects of anxiety/fear being rated as early as 60 minutes in some participants, but as late as
180 or 240 minutes in others (see Figure 2 for illustrative data). Forty-four percent of participants (8 of 18) reported delusions or paranoid
thinking sometime during the session; such episodes occurred in 7 of 8 of these participants after the 30 mg/70 kg dose and in 1 of 7 after 20
mg/70 kg dose. Examples of delusions included the belief that a child or loved one had died during the time of the session, or that the session
monitors were malevolently manipulating the participant. Three of 8 volunteers who had such episodes were those who also rated extreme
fear or fear of insanity. Inspection of the data indicated that delusions and extreme ratings of fear/anxiety were not differentially affected by
dose sequence.

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Fig. 2

Time-course of monitor ratings of anxiety or fearfulness after 30 mg/70 kg in the five volunteers whose mean ratings were 2.0 or higher at one or more time point. Data
points are mean ratings of the two session monitors. Different symbols represent different volunteers. The figure illustrates the unpredictable time-course of anxiety or
fear across the session.
These psychological struggles did not affect the overall rate of having “complete” mystical experiences as rated by volunteers at the end of the
session day. Five of seven (71%) of participants reporting extreme fear, insanity or feeling trapped provided data consistent with “complete”
mystical experiences, and 4 of 8 (50%) of participants who had delusions or paranoid thinking provided data consistent with “complete” mys‐
tical experiences. These rates of “complete” mystical experience are generally similar to the rate for the group as a whole (56%). Although psy‐
chological struggles did not affect the overall rate of “complete” mystical experience, it should be noted that neither of the two volunteers who
had the most sustained anxiety during the 30 mg/70 kg session (Figure 2, square and circle symbols) had a “complete” mystical experience. In
addition to not affecting rate of mystical experience, inspection of the data indicated no consistent relationship between psychological struggle
and subsequent ratings of the session as having personal meaning and spiritual significance. No volunteer rated the overall experience as hav‐
ing decreased her or his sense of well-being or life satisfaction.

The volunteer who had the most sustained anxiety during the 30 mg/70 kg dose session (Fig. 2, square symbols) provides an interesting case
example. Likely as a consequence of the sustained psychological struggle during the session, this volunteer also had the lowest mystical experi‐
ence rating immediately after the session of all 18 volunteers studied. Immediately after the session, this volunteer, who for decades had held
reincarnation as part of her worldview, reported that it was the worst experience of her life and that she would rather spend three lifetimes
on a mountaintop meditating than repeat what she had just experienced during the session. Although she considered dropping out of the
study after this first session and she remained hesitant to receive psilocybin again, over the next several weeks she increasingly felt that she
had learned something useful from the experience. At 1 month, she rated the experience as having slight spiritual significance and as having
slightly increased her sense of well-being or life satisfaction. Because she remained curious about the effects of psilocybin, she decided to con‐
tinue to participate in the study. She received 20 mg/70 kg psilocybin on the second session. In contrast to her first session, her post-session
ratings fulfilled criteria for a “complete” mystical experience and, at 1 month, she retrospectively rated this experience as the single most per‐
sonally meaningful and spiritually significant of her life.

Persisting effects assessed one month after sessions

Persisting Effects Questionnaire As shown in Table 4, psilocybin produced significant and generally monotonically increasing effects as a func‐
tion of dose in positive ratings of attitudes about life, attitudes about self, mood, social effects, and behavior. Negative ratings of these same di‐
mensions were very low and did not differ across the doses except for negative attitudes about self that showed small but significant increases
at the two lowest doses. Table 4 also shows that ratings of the personal meaningfulness and spiritual significance of the experience, and rat‐
ings of well-being or life satisfaction were significant and a monotonic increasing function of dose. Of the persisting effects measures shown in
Table 4, all six of the positive subscales (attitudes about life, attitudes about self, mood, altruism, behavior, and spirituality) and one of the
three questions (sense of well-being/life satisfaction) showed significant Dose x Dose Sequence interactions. Inspection of these data showed
that this effect was primarily due to the ascending dose sequence producing relatively larger effects at the 20 and 30 mg/70 kg doses and rela‐
tively smaller effects at lower doses compared to the descending dose sequence. Figure 3 shows this effect for two representative measures:
persisting effects on well-being/life satisfaction and on positive mood.

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Fig. 3

Effects of dose sequence on ratings of persisting effects of well-being/life satisfaction and positive mood completed one month after sessions. Data points are means and
brackets show 1 SEM for participants in the ascending dose sequence (triangles) and the descending dose sequence (circles). Dose x Dose Sequence interactions were sig‐
nificant. Asterisks indicate a significant difference between the ascending and descending dose sequence at the indicated dose (Fisher’s LSD post hoc).
Table 4

Volunteer ratings of persisting effects 1 month and 14 months after sessions *

1 Month after Sessions 14 Month

Follow-up
Questionnaire and Subscale Description Psilocybin Dose (mg/70 kg)
(20 or 30
† † † † †
0 5 10 20 30 mg/70 kg) ‡

Persisting Effects Questionnaire

Positive attitudes about life 33.3 (6.6) 45.9 (5.6)a 50.3 (6.6)a 62.2 (5.6)b 65.9 (5.9)b 68.8 (4.8)

Negative attitudes about life 0.6 (0.4) 0.8 (0.5) 1.4 (0.6) 0.8 (0.4) 0.6 (0.4) 3.2 (1.3)

Positive attitudes about self 31.9 (6.1) 44.4 (5.4)a 46.5 (6.2)a,c 54.2 (5.5)b,c 58.9 (6.0)b 61.1 (5.4)

Negative attitudes about self 0.1 (0.1) 2.1 (0.6)a 1.5 (0.6)a,b 0.7 (0.5)b,c 1.1 (0.4)a,c 2.3 (0.9)

Positive mood changes 26.8 (5.4) 36.4 (5.1)a 42.9 (6.2)a,b 51.3 (5.8)b 52.7 (6.0)b 55.3 (5.9)

Negative mood changes 0.3 (0.2) 0.4 (0.3) 1.1 (0.7) 0.8 (0.4) 0.2 (0.2) 1.7 (0.8)

Altruistic/positive social effects 28.3 (6.0) 37.1 (5.3)a 42.4 (6.5)a 52.0 (5.9)b 54.6 (5.7)b 54.1 (6.5)

Antisocial/negative social effects 0.2 (0.2) 1.3 (0.9) 0.9 (0.7) 1.2 (0.9) 0.8 (0.9) 2.5 (0.9)

Positive behavior changes 35.6 (8.1) 45.6 (6.4)a 58.9 (8.7)a,b 57.8 (7.6)a,b 71.1 (6.7)b 68.9 (5.9)

Negative behavior changes 0.0 (0.0) 2.2 (2.3) 2.2 (2.3) 0.0 (0.0) 0.0 (0.0) 0.0 (0.0)

Increased spirituality 31.1 (6.2) 42.3 (6.7)a 48.2 (7.0)a,b 57.9 (6.2)b 58.3 (5.8)b 71.6 (6.3)

Decreased spirituality 0.4 (0.3) 0.2 (0.2) 0.6 (0.3) 0.6 (0.4) 0.8 (0.4) 1.1 (0.6)

How personally meaningful was the

3.33 (0.40) 5.06 (0.36)a 5.56 (0.43)a 6.67 (0.31)b 6.67 (0.34)b 7.22 (0.22)
experience? (max score=8)

How spiritually significant

2.72 (0.35) 3.28 (0.27)a 3.94 (0.32)a,c 4.67 (0.31)b,c 4.94 (0.33)b 5.28 (0.23)
was the experience? (max score=6)

Did the experience change your sense of

1.11 (0.23) 1.72 (0.25)a 2.0 (0.25)a,c 2.5 (0.22)b 2.39 (0.21)b,c 2.39 (0.22)
well-being or life satisfaction? (max score=3)
 *
Data are mean scores with 1 SEM shown in parentheses (N=18); data on attitudes, mood, altruistic/social effects, and behavior changes are expressed as percentage of
maximum possible score; data for the final three questions are raw scores
†
Data in these columns show rating data 1 month after the indicated dose of psilocybin; within the same row for these columns, bold font indicates significant difference
from 0 mg/70 kg; for active doses (Fisher’s LSD p<0.05), values not sharing a common letter are significantly different (Fisher’s LSD p<0.05)
‡Data in this column show ratings at the 14 month follow-up; ratings were completed with respect to experiences during either or both the 20 and 30 mg/70 kg dose
sessions (see Methods); no statistical comparison was conducted

Table 5 shows the percentages of volunteers who endorsed specific outcomes on four items on the Persisting Effects Questionnaire.
Endorsement increased as a function of dose. Notably, 61% of volunteers considered the psilocybin experience during either or both the 20
and 30 mg/70 kg sessions to have been the single most spiritually significant of their lives, with 83% rating it in their top 5. Consistent with
this, 94%, and 89% of volunteers, respectively, indicated that the experiences on those same sessions increased their well-being or life satisfac‐
tion and positively changed their behavior at least moderately. Of the 90 total sessions, none were rated as having decreased well-being or life
satisfaction.
Table 5

Percentage of volunteers endorsing specific outcomes on four persisting effects items 1 month and 14 months after sessions *

1 Month after Sessions 14 Month

Follow-up
Questionnaire Items Psilocybin Dose (mg/70 kg)
(20 or 30
† † † † † ‡
0 5 10 20 30 20 or 30 mg/70 kg)**

How personally meaningful was the experience?

Single most meaningful experience of life 0.0 0.0 5.6 16.7 33.3 44.4 38.9

Top 5 most meaningful, including single most 0.0 11.1 33.3 77.8 61.1 77.8 94.4

How spiritually significant was the experience?

Single most spiritually significant experience of life 0.0 0.0 5.6 27.8 44.4 61.1 44.4

Top 5 most spiritually significant, including single most 11.1 11.1 44.4 66.7 77.8 83.3 94.4

Did the experience change your sense of well-being or

life satisfaction?

Increased well-being/life satisfaction (very much) 5.6 27.8 38.9 72.2 55.6 77.8 61.1

Increased well-being/life satisfaction (moderately or very much) 38.9 55.6 72.2 83.3 88.9 94.4 83.3

Your behavior changed in ways you would consider positive since

the experience.

Positive behavioral change (strong or extreme) 22.2 16.7 50.0 38.9 55.6 55.6 44.4

Positive behavioral change (moderate, strong or extreme) 33.3 50.0 61.1 61.1 88.9 88.9 88.9

*
Data in table show the percentage of volunteers endorsing the specific outcome
†Data in these columns are the percentage of volunteers endorsing the specific outcome 1 month after the indicated dose of psilocybin; within the same row for these
columns, bold font indicates significant difference in pair-wise comparisons to 0 mg/70 kg (Cochran’s Q showed p<.001 for all variables; planned comparisons
performed with Wald test; see Methods for details)
 ‡
Data in this column are the percentage of volunteers endorsing the specific outcome 1 month after either or both the 20 and 30 mg/70 dose sessions; bold font indicates
significant difference in pair-wise comparisons to 0 mg/70 kg (Cochran’s Q showed p<.05 for all variables; planned comparisons performed with Wald test; see Methods
for details)
**
Data in this column are the percentage of volunteers at 14 month follow-up endorsing the specific outcome with respect to experiences during either or both the 20 and
30 mg/70 kg dose sessions (see Methods); each value in this column was significantly greater than the value at 0 mg/70 kg (as indicated by bold font) but was not
significantly different from the value at 20 or 30 mg/kg at 1 month (Cochran’s Q showed p<.05 for all variables; planned comparisons performed with Wald test; see
Methods for details)

Retrospective persisting effects assessed at 14-month follow-up

The right-most columns of Tables 3, ​4 and ​5 show that the retrospective ratings at the 14-month follow-up on the States of Consciousness
Questionnaire mystical experience items and on the Persisting Effects Questionnaire were undiminished from ratings obtained 1 month after
sessions. No participant rated that their behavior was affected negatively or that their well-being/life satisfaction was decreased as a result of
the psilocybin experiences on the two highest dose sessions. The analysis of the States of Consciousness Questionnaire mystical experience
items showed significant Condition x Dose Sequence Interactions on Internal Unity, Mood, and Total score. Inspection of these data showed
that the ascending dose sequence was associated with relatively larger effects at 30 mg/70 kg both post-session and at 14-month follow-up.

When asked at 14 months which of the five sessions seemed strongest, 83% and 17% of volunteers indicated the session associated with 30
and 20 mg/70 kg, respectively; most personally meaningful (44%, 44%, and 11% at 30, 20, and 10 mg/70 kg, respectively); most spiritually
significant (56%, 33%, and 11% at 30, 20, and 10 mg/70 kg, respectively); and which session they would want to repeat if they had an oppor‐
tunity to do so (67%, 28% and 6% at 30, 20 and 10 mg/70 kg, respectively). Consistent with the flattened dose-effect curve for persisting ef‐
fects shown in Fig. 3, most volunteers in the ascending dose sequence rated the highest dose session (30 mg/70 kg) as the most personally
meaningful (67%) and spiritually significant (78%) of the five sessions; in contrast, a smaller proportion of volunteers in the descending se‐
quence rated the highest dose session as most personally meaningful (22%) and spiritually significant (22%). The mean ± 1 SEM dose of the
sessions that were rated as being the most personally meaningful were 25.6 ± 2.6 and 21.1 ± 1.8 in the ascending and descending dose se‐
quence, respectively (N.S.); similar ratings of spiritual significance were 27.8 ± 2.6 and 21.1 ± 1.5 respectively (p<.05, t-test).

Also at the 14-month follow-up, participants provided written descriptions, based on their memories of their two highest dose sessions, of
how they thought their behavior changed in response to those experiences. As summarized in Table 6, only 2 volunteers indicated no positive
change in their behavior. The domains of change most frequently cited were better social relationships with family and others, increased physi‐
cal and psychological self-care, and increased spiritual practice.
Table 6

Self-reported behavior change. Verbatim written comments about the nature of behavioral changes volunteers attributed to either or both the two highest dose psilocybin
session experiences in the Retrospective Questionnaire completed at the 14-month follow-up.
 Volunteer Verbatim Comments

201 Virtually eliminated all religious practices; much more spiritual now. Accepting of my
parents and have a
more open and honest dialogue with them. Less judgmental and more open hearted. Taken
a more
active role in pursuing what I want for myself.

202 I have an increased commitment to spiritual practices; I think my heart is more open to all
interactions
with other people; more aware of choices, take time to pause and choose, more breaks;
better
boundaries at work and personal relationships

205 I have a stronger desire for devotion, have increased yoga practice and prayer. I have better
interaction
with close friends and family and with acquaintances and strangers… I feel more certain of
my career as
an author. I need less food to make me full. My alcohol use has diminished dramatically… I
consider
myself to be better [at self-care] now than before the study…

206 Feel closer to family and friends. Incorporating Ayurvedic theory into diet and self care.
[Also changed her
meditation and yoga practice]

207 More regular meditation; more mindful with family; more generous with strangers; started
new yoga
practice; more relaxation of pace of change

210 I feel that I relate better in my marriage. There is more empathy - a greater understanding of

Longitudinal measures assessed at baseline, after session 5, and at 14-month follow-up

Longitudinal measures of mystical experience, of death transcendence, and of community observer ratings of changes in participants’ behav‐
ior and attitudes showed effects generally consistent with the previously described persisting effects. After session 5 and at 14-month follow-
up, the total score (as well as each of the three subscales) of the Mysticism Scale (Lifetime) was significantly higher than at screening (217.9 ±
10.8, 264.1 ± 6.8, and 260.4 ± 7.6, means and SEMs for total scores at screening, post-session 5, and 14-month follow-up, respectively)
(Planned comparisons, p<.0001). The Religious subscale of the Death Transcendence Scale, which assesses a sense of continuity after death,
showed similar increases (28.72 ± 1.57, 31.00 ±, 0.99, and 31.28 ± 1.07, means and SEMs for screening, post-session 5, and 14-month follow-
up, respectively)(Planned comparisons, p<.05). The other subscales were not significant. For the community observer ratings of participants’
behavior and attitudes, change scores from those taken about 1 week after study enrollment (means ± SEMs) were significant both after ses‐
sion 5 (8.85 ± 1.64) and at the 14-month follow-up (5.36 ± 1.68)(Planned comparisons, p<.001).

Post-study monitor ratings of enduring effects in participants

The post-study monitor ratings of enduring effects in participants were consistent with the participant self-ratings and the community ob‐
server ratings of changes in participants’ behavior and attitudes. Mean ± SEM of monitor ratings of the volunteers’ personal well-being/life
satisfaction, quality of social relationships, and sense of spirituality were all in the positive direction (2.33 ± 0.14, 1.64 ± 0.14, and 2.41 ± 0.15,
respectively).

Open-ended clinical interview at the 14-month follow-up

An open-ended clinical interview at the 14-month follow-up was conducive to the spontaneous reporting of possible persisting adverse events.
There were no reports of bothersome or clinically significant persisting perception phenomena sometimes attributed to hallucinogen use.
Likewise, there were no reports of any non-study use of hallucinogens since study enrollment. All 18 volunteers appeared to continue to be
psychiatrically healthy, high-functioning, productive members of society.

Discussion

The present study demonstrated orderly dose-related increases in the effects of psilocybin on volunteer and observer ratings of drug effect
and on the cardiovascular measures of blood pressure and heart rate. Notably, even the 5 mg/70 kg (71 μg/kg) dose of psilocybin produced
significant subjective, physiological, and observer-rated effects. This is the lowest dose of psilocybin demonstrated to produce significant ef‐
fects. A previous study showed dose-related effects of psilocybin at doses of 45, 115, 215, and 315 μg/kg, however did not show statistically
significant effects at the lowest dose (Hasler et al. 2004). Consistent with previous findings, the present study showed orderly time-related ob‐
server-rated and cardiovascular effects during the session, with significant effects at the highest doses generally occurring at 30-60 minutes,
peaking at 90-180 minutes, and decreasing toward pre-drug levels over the remainder of the session (Griffiths et al. 2006).

The present study extends previous observations showing that psilocybin can occasion mystical-type experiences having sustained personal
and spiritual significance (Pahnke 1963; Doblin 1991; Griffiths et al. 2006, 2008). Two volunteer-rated measures of mystical-type experience
completed at the end of the session days showed dose-related increases, with 72% of volunteers fulfilling criteria for having had a “complete”
mystical experience at either or both of the two highest dose sessions. Retrospective ratings of mystical experience and spiritual significance
did not diminish in time. One month after either or both the two highest dose sessions, 83% of participants rated the experience as the single
most or among the 5 most spiritually significant experiences of their life. At the 14-month follow-up, this number was even higher (94%).
Likewise, at 14 months, retrospective ratings of mystical experience at the highest dose were generally slightly higher than at the 1-month rat‐
ing time. Finally, longitudinal measures of lifetime mystical experience and of death transcendence (Religious subscale) were significantly in‐
creased over screening levels at both one month and 14 months after the final session. The significant increase in the Religious subscale of the
Death Transcendence Scale is notable in this group of healthy volunteers because questions in this subscale assess a sense of continuity after
death (e.g. Death is a transition to something even greater than this life; Death is never just an ending, but a part of a process). This effect may
be relevant to the proposed palliative effects of psilocybin and similar hallucinogens in treating existential anxiety in terminal illness (Kast
1967; Richards et al. 1972; Grob et al. 2011).

The present study also extends previous observations indicating that psilocybin can occasion persisting positive changes in attitudes, mood,
life satisfaction, behavior, and altruism/social effects (Griffiths et al. 2006, 2008). All of these domains showed dose-related increases one
month after sessions, with effects at the highest doses sustained at the 14-month follow-up. One month after sessions at either or both the two
highest dose sessions, 94% of volunteers endorsed that the experience increased their sense of well-being or life satisfaction moderately or
very much, and 89% rated moderate or higher changes in positive behavior. At the 14-month follow-up, these ratings remained high. The types
of behavior change most frequently cited by volunteers were better social relationships with family and others, increased physical and psycho‐
logical self-care, and increased spiritual practice (Table 6). Ratings by community observers before and after the study as well as ratings by
study monitors after the study were consistent with the persisting positive changes in behavior and attitudes claimed by the volunteers. The
persisting positive changes, particularly in attitudes, mood, and life satisfaction, occasioned by psilocybin appear similar in kind and breadth to
the enduring changes reported in case studies of individuals who have had spontaneously-occurring mystical- or insightful-types of experi‐
ences (Miller and C’ de Baca, 2001).

A novel aspect of the present study was that it compared effects in volunteers who received the four active psilocybin doses in either an as‐
cending or a descending dose sequence. Although the acute measures of psilocybin effects were not affected by the dose sequence, volunteer-
rated positive changes in attitudes and behavior assessed 1 month after each session showed Dose x Dose Sequence interactions reflecting
relatively larger effects at the highest psilocybin doses than the lower doses in the ascending dose sequence compared to the descending se‐
quence (Figure 2). Analogous differences occurred at the 14-month follow-up assessment on the mystical experience items of the States of
Consciousness Questionnaire and on retrospective ratings of the personal meaning and spiritual significance associated with various session
doses. Overall, these findings suggest that the ascending dose sequence is somewhat more likely than the descending sequence to produce
long-lasting positive changes in attitudes, behavior, and remembered mystical-type experiences. Thus it appears that having experience with
lower doses facilitates the likelihood of having sustained positive effects after a high dose of psilocybin. The biological or psychological mecha‐
nisms underlying this effect are unknown. This finding suggesting an advantage of an ascending dose sequence may have clinical application in
the design of therapeutic studies of psilocybin (Griffiths and Grob, 2010; Grob et al. 2011). It is noteworthy, however, that this finding is con‐
trary to some older recommendations of psychotherapists who administered classic hallucinogens. Specifically, in one report (Blewett and
Chwelos, 1959) psychotherapists inferred from their clinical experience that a single high-dose overwhelming experience was more therapeu‐
tic than an approach that began with a small doses and gradually increased the dose over successive experiences.

Also of relevance to the design of future research trials with psilocybin, the present study provides information about the relative likelihood of
different doses of psilocybin to occasion acute adverse subjective effects as well as mystical-type effects having persisting positive effects. The
acute anxiety/fear-producing effects of psilocybin, as assessed by monitor and volunteer ratings, increased with increasing doses. Thirty-nine
percent of volunteers reported extreme fear, fear of insanity, or feeling trapped sometime during the session (0 at placebo or the two lower
doses, 1 at 20 mg/70 kg, and 6 at 30 mg/70 kg). Furthermore, 44% of volunteers reported delusions or paranoid thinking sometime during
the session (0 at placebo and the two lower doses, 1 at 20 mg/70 kg, and 7 at 30 mg/70 kg). In the present study, such negative effects were
well managed with reassurance in the highly supportive setting. Interestingly, these psychological struggles did not generally affect rates of
having “complete” mystical experiences, possibly because the negative feelings were most often of short duration. However, under conditions
in which volunteers are less well screened and psychologically prepared, or sessions are not as well supervised, there could be a possibility
that extreme anxiety and/or delusion could be prolonged and result in dangerous behavior. Under such conditions, administration of doses
higher than about 20 mg/70 would be inadvisable. The unpredictable time-course across the session of anxiety or fear (Fig.2) underscores
the importance that session monitors remain vigilant throughout the session. Furthermore, the unpredictable time-course of anxiety, in combi‐
nation with the finding that even experienced session monitors cannot rate with high reliability whether or not psilocybin has been adminis‐
tered (Griffiths et al., 2006), suggests the potential risk of the recommendation by some psychotherapists that a “booster” dose of a classic hal‐
lucinogen should be administered relatively shortly after the initial dose if the effects are less than expected (Blewett and Chwelos, 1959;
Stolaroff 1997).

In a therapeutic or other research trial, the possibility of such potentially adverse effects should be considered in relationship to the potential
persisting positive effects. The proportion of volunteers having “complete” mystical-type experiences, which likely mediate persisting positive
effects (Richards et al. 1977; Griffiths et al. 2008), as well as the persisting positive effects (Table 4 and ​5) were generally an increasing func‐
tion of dose, with the percentage change from 20 to 30 mg/70 kg varying widely (−23% to a +99%), with a mean of +17%. However, endorse‐
ment of having had a “complete” mystical experience, or of having had the single most spiritually significant experience of his/her life in‐
creased 25% and 60%, respectively from 20 to 30 mg/70 kg. Likewise, endorsement of moderate to extreme positive behavioral change, which
may be the most relevant outcome measure in some therapeutic trials, increased 45% from 20 to 30 mg/70 kg. Thus, in addition to consider‐
ing the extent of screening and support provided to volunteers, the decision to administer psilocybin doses higher than about 20 mg/70 kg
should be made on the basis of the type of outcome desired.

The present study provided no evidence of adverse effects of high dose psilocybin exposure other than the episodes of psychological struggle
during some portion of the time of psilocybin action. This should not be interpreted to suggest that casual use of high dose psilocybin is safe. It
is important to recognize that the present study was conducted in carefully screened volunteers who received ample preparation before ses‐
sions, were closely monitored during sessions, and had some continuing contact with study staff after sessions (see Johnson et al., 2008 for
detailed safety guidelines for minimizing risks of high dose hallucinogen exposure in human research). The reported potential risks of hallu‐
cinogen exposure include: (1) panic or fear reactions resulting in dangerous behavior during the time of drug action; (2) precipitation or exac‐
erbation of enduring psychiatric conditions; (3) long-lasting perceptual disturbances and (4) development of an abusive pattern of hallucino‐
gen use (Abraham, et al., 1996; Halpern and Pope, 1999; Johnson, et al., 2008).

The generalizability of the results of the present study is limited by the study population, a group of hallucinogen-naïve, well-educated, psycho‐
logically stable, mostly middle-aged adults, most of whom reported at least weekly participation in religious or spiritual activity. It would be
particularly interesting to determine whether volunteers who identified as atheist or agnostic would be as likely to have mystical-type experi‐
ences and whether they would ascribe spiritual significance to such experiences. It would also be interesting to compare hallucinogen-naïve
volunteers with past users to provide information about whether the novelty of effects in naïve volunteers contributes to the high persisting
ratings of personal meaning and spiritual significances.

Overall, the present study shows that psilocybin can dose-dependently occasion mystical-type experiences having persisting positive effects on
attitudes, mood, and behavior. The observations that episodes of extreme fear, feeling trapped, or delusions occur at the highest dose in al‐
most 40% of volunteers, that anxiety and fear have an unpredictable time-course across the session, and that an ascending sequence of dose
exposure may be associated with long-lasting positive changes have implications for the design of therapeutic trials with psilocybin.
Considering the rarity of spontaneous mystical experiences in the general population, the finding that more than 70% of volunteers in the cur‐
rent study had “complete” mystical experiences suggests that most people have the capacity for such experiences under appropriate condi‐
tions and, therefore, such experiences are biologically normal.
Acknowledgements

Conduct of this research was supported by grants from the Council on Spiritual Practices, the Heffter Research Institute, and the Betsy Gordon
Foundation. Effort for Roland Griffiths, Ph.D. in writing this paper was partially provided by NIH grant RO1DA03889. We thank David Nichols,
Ph.D. for synthesizing the psilocybin, Mary Cosimano, M.S.W. for her role as a primary session monitor, Maggie Klinedinst for data manage‐
ment, and Linda Felch M.A. and Paul Nuzzo, M.A. for statistical analyses. We also thank Larry Carter, Ph.D., Ryan Lanier, Ph.D., Benjamin McKay,
Chad Ressig, Ph.D., and Ryan Vandrey, Ph.D. for serving as assistant session monitors. The study was conducted in compliance with United
States laws.

Contributor Information

R. R. Griffiths, Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine 5510 Nathan Shock Drive
Baltimore, MD 21224-6823, USA; Department of Neuroscience Johns Hopkins University School of Medicine 5510 Nathan Shock Drive
Baltimore, MD 21224-6823, USA.

M.W. Johnson, Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine 5510 Nathan Shock Drive
Baltimore, MD 21224-6823, USA.

W. A. Richards, Department of Psychiatry Johns Hopkins Bayview Medical Center 2516 Talbot Road Baltimore, MD 21216-2032.

B.D. Richards, Department of Psychiatry Johns Hopkins Bayview Medical Center 2516 Talbot Road Baltimore, MD 21216-2032.

U. McCann, Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine 5510 Nathan Shock Drive
Baltimore, MD 21224-6823, USA.

R. Jesse, Council on Spiritual Practices Box 460220 San Francisco, CA 94146-0220.

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